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Functional Consequences of Disease-Associated Mutations in TNFR1 Elucidated by Transcriptome Analysis

  • Susana L. Rebelo
  • Paul M. Radford
  • Susan E. Bainbridge
  • Ian Todd
  • Patrick J. Tighe
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 691)

Abstract

Mutations in the TNFRSF1A (TNF receptor 1) gene cause the autosomal dominant, autoinflammatory tumour necrosis factor receptor-associated periodic syndrome (TRAPS). TRAPS is characterised by recurring attacks of fever, abdominal pain, arthralgia, myalgia, conjunctivitis, migratory skin lesions and systemic amyloidosis. The exact mechanism by which this periodic fever is triggered has yet to be elucidated. Over the last decade, several studies with patient and transfected cells have attempted to dissect the molecular mechanisms induced by mutant receptor expression and resulted in several hypotheses being proposed to explain the disease pathogenesis. Our recent data suggest that cellular expression of mutant TNFR1 per se is a signal for inflammatory changes. We hypothesised that different mutations can lead to the activation of distinct intracellular signalling pathways with a pro-inflammatory outcome in a TNF-independent fashion. To test this hypothesis, we investigated how different TNFR1 mutants affect global gene expression in epithelial and endothelial cell models. Compared to WT, cells expressing mutant TNFR1 showed downregulation of genes that suppress immune responses and upregulation of multiple genes involved in mediating inflammation. Both cell type-specific and mutant-specific profiles were identified. We have identified a number of novel genes that may play a role in the pathogenesis of TRAPS. Further studies with patient cells and in vivo models are needed to clarify relevance for disease pathogenesis and assist in the identification of new drug targets.

Keywords

Global Gene Expression Patient Cell Periodic Fever Autoinflammatory Disorder TNFRSF1A Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M, Mansfield E, Gadina M, Karenko L, Pettersson T, McCarthy J, Frucht DM, Aringer M, Torosyan Y, Teppo AM, Wilson M, Karaarslan HM, Wan Y, Todd I, Wood G, Schlimgen R, Kumarajeewa TR, Cooper SM, Vella JP, Amos CI, Mulley J, Quane KA, Molloy MG, Ranki A, Powell RJ, Hitman GA, O’Shea JJ, and Kastner DL (1999) Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97:133–144CrossRefPubMedGoogle Scholar
  2. 2.
    Masters SL, Lobito AA, Chae J, and Kastner DL (2006) Recent advances in the molecular pathogenesis of hereditary recurrent fevers. Curr Opin Allergy Clin Immunol 6:428–433CrossRefPubMedGoogle Scholar
  3. 3.
    Masters SL, Simon A, Aksentijevich I, and Kastner DL (2009) Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol 27:621–668CrossRefPubMedGoogle Scholar
  4. 4.
    Sarrauste de Menthiere C, Terriere S, Pugnere D, Ruiz M, Demaille J, and Touitou I (2003) INFEVERS: the Registry for FMF and hereditary inflammatory disorders mutations. Nucleic Acids Res 31:282–285CrossRefGoogle Scholar
  5. 5.
    Todd I, Radford PM, Draper-Morgan KA, McIntosh R, Bainbridge S, Dickinson P, Jamhawi L, Sansaridis M, Huggins ML, Tighe PJ, and Powell RJ (2004) Mutant forms of tumour necrosis factor receptor I that occur in TNF-receptor-associated periodic syndrome retain signalling functions but show abnormal behaviour. Immunology 113:65–79CrossRefPubMedGoogle Scholar
  6. 6.
    Huggins ML, Radford PM, McIntosh RS, Bainbridge SE, Dickinson P, Draper-Morgan KA, Tighe PJ, Powell RJ, and Todd I (2004) Shedding of mutant tumor necrosis factor receptor superfamily 1A associated with tumor necrosis factor receptor-associated periodic syndrome: differences between cell types. Arthritis Rheum 50:2651–2659CrossRefPubMedGoogle Scholar
  7. 7.
    Todd I, Radford PM, Daffa N, Bainbridge SE, Powell RJ, and Tighe PJ (2007) Mutant tumor necrosis factor receptor associated with tumor necrosis factor receptor-associated periodic syndrome is altered antigenically and is retained within patients’ leukocytes. Arthritis Rheum 56:2765–2773CrossRefPubMedGoogle Scholar
  8. 8.
    Rebelo SL, Bainbridge SE, Amel-Kashipaz MR, Radford PM, Powell RJ, Todd I, and Tighe PJ (2006) Modeling of tumor necrosis factor receptor superfamily 1A mutants associated with tumor necrosis factor receptor-associated periodic syndrome indicates misfolding consistent with abnormal function. Arthritis Rheum 54:2674–2687CrossRefPubMedGoogle Scholar
  9. 9.
    Lobito AA, Kimberley FC, Muppidi JR, Komarow H, Jackson AJ, Hull KM, Kastner DL, Screaton GR, and Siegel RM (2006) Abnormal disulfide-linked oligomerization results in ER retention and altered signaling by TNFR1 mutants in TNFR1 associated periodic fever syndrome (TRAPS). Blood 108:1320–1327CrossRefPubMedGoogle Scholar
  10. 10.
    Aganna E, Hammond L, Hawkins PN, Aldea A, McKee SA, van Amstel HK, Mischung C, Kusuhara K, Saulsbury FT, Lachmann HJ, Bybee A, McDermott EM, La Regina M, Arostegui JI, Campistol JM, Worthington S, High KP, Molloy MG, Baker N, Bidwell JL, Castaner JL, Whiteford ML, Janssens-Korpola PL, Manna R, Powell RJ, Woo P, Solis P, Minden K, Frenkel J, Yague J, Mirakian RM, Hitman GA, and McDermott MF (2003) Heterogeneity among patients with tumor necrosis factor receptor-associated periodic syndrome phenotypes. Arthritis Rheum 48:2632–2644CrossRefPubMedGoogle Scholar
  11. 11.
    Hull KM, Drewe E, Aksentijevich I, Singh HK, Wong K, McDermott EM, Dean J, Powell RJ, and Kastner DL (2002) The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder. Medicine (Baltimore) 81:349–368CrossRefGoogle Scholar
  12. 12.
    Ravet N, Rouaghe S, Dode C, Bienvenu J, Stirnemann J, Levy P, Delpech M, and Grateau G (2006) Clinical significance of P46L and R92Q substitutions in the tumor necrosis factor superfamily 1A gene. Ann Rheum Dis 65:1158–1162CrossRefPubMedGoogle Scholar
  13. 13.
    Todd I, Tighe PJ, and Powell RJ (2005) TNF AND TNF receptors in TRAP. Curr Med Chem Anti Inflamm Anti Allergy Agents 4:577–586CrossRefGoogle Scholar
  14. 14.
    Stojanov S, Dejaco C, Lohse P, Huss K, Duftner C, Belohradsky BH, Herold M, and Schirmer M (2008) Clinical and functional characterisation of a novel TNFRSF1A c.605T>A/V173D cleavage site mutation associated with tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), cardiovascular complications and excellent response to etanercept treatment. Ann Rheum Dis 67:1292–1298CrossRefPubMedGoogle Scholar
  15. 15.
    Lamprecht P, Moosig F, Adam-Klages S, Mrowietz U, Csernok E, Kirrstetter M, Ahmadi-Simab K, Schroder JO, and Gross WL (2004) Small vessel vasculitis and relapsing panniculitis in tumour necrosis factor receptor associated periodic syndrome (TRAPS). Ann Rheum Dis 63:1518–1520CrossRefPubMedGoogle Scholar
  16. 16.
    Trost S, and Rose CD (2005) Myocarditis and sacroiliitis: 2 previously unrecognized manifestations of tumor necrosis factor receptor associated periodic syndrome. J Rheumatol 32:175–177PubMedGoogle Scholar
  17. 17.
    Kumpfel T, Hoffmann LA, Pellkofer H, Pollmann W, Feneberg W, Hohlfeld R, and Lohse P (2008) Multiple sclerosis and the TNFRSF1A R92Q mutation: clinical characteristics of 21 cases. Neurology 71:1812–1820CrossRefPubMedGoogle Scholar
  18. 18.
    Hoffmann LA, Lohse P, Konig FB, Feneberg W, Hohlfeld R, and Kumpfel T (2008) TNFRSF1A R92Q mutation in association with a multiple sclerosis-like demyelinating syndrome. Neurology 70:1155–1156CrossRefPubMedGoogle Scholar
  19. 19.
    Horiuchi T, Tsukamoto H, Mitoma H, Miyagawa H, Tamimoto Y, Yoshizawa S, Harada M, Hayashi K, Hashimura C, Oribe M, and Okamura S (2004) Novel mutations in TNFRSF1A in patients with typical tumor necrosis factor receptor-associated periodic syndrome and with systemic lupus erythematosus in Japanese. Int J Mol Med 14:813–818PubMedGoogle Scholar
  20. 20.
    Harambat J, Desjonqueres M, Garaix F, Cochat P, Ranchin B, Cimaz R, Dode C, and Bouvier R (2008) First report of rapidly progressive glomerulonephritis in tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum 58:3275–3276CrossRefPubMedGoogle Scholar
  21. 21.
    Nowlan ML, Drewe E, Bulsara H, Esposito N, Robins RA, Tighe PJ, Powell RJ, and Todd I (2006) Systemic cytokine levels and the effects of etanercept in TNF receptor-associated periodic syndrome (TRAPS) involving a C33Y mutation in TNFRSF1. Rheumatology A (Oxford) 45:31–37CrossRefGoogle Scholar
  22. 22.
    Rebelo SL, Amel-Kashipaz MR, Radford PM, Bainbridge SE, Fiets R, Fang J, McDermott EM, Powell RJ, Todd I, and Tighe PJ (2009) Novel markers of inflammation identified in tumor necrosis factor receptor-associated periodic syndrome (TRAPS) by transcriptomic analysis of effects of TRAPS-associated tumor necrosis factor receptor type I mutations in an endothelial cell line. Arthritis Rheum 60:269–280CrossRefPubMedGoogle Scholar
  23. 23.
    Morbach H, Richl P, Stojanov S, Lohse P, and Girschick HJ (2009) Tumor necrosis factor receptor 1-associated periodic syndrome without fever: cytokine profile before and during etanercept treatment. Rheumatol Int 30:207–212CrossRefGoogle Scholar
  24. 24.
    Jesus AA, Oliveira JB, Aksentijevich I, Fujihira E, Carneiro-Sampaio MM, Duarte AJ, and Silva CA (2008) TNF receptor-associated periodic syndrome (TRAPS): description of a novel TNFRSF1A mutation and response to etanercept. Eur J Pediatr 167:1421–1425CrossRefPubMedGoogle Scholar
  25. 25.
    Drewe E, Huggins ML, Morgan AG, Cassidy MJ, and Powell RJ (2004) Treatment of renal amyloidosis with etanercept in tumour necrosis factor receptor-associated periodic syndrome. Rheumatology (Oxford) 43:1405–1408CrossRefGoogle Scholar
  26. 26.
    Sacre K, Brihaye B, Lidove O, Papo T, Pocidalo MA, Cuisset L, and Dode C (2008) Dramatic improvement following interleukin 1beta blockade in tumor necrosis factor receptor-1-associated syndrome (TRAPS) resistant to anti-TNF-alpha therapy. J Rheumatol 35:357–358PubMedGoogle Scholar
  27. 27.
    Gattorno M, Pelagatti MA, Meini A, Obici L, Barcellona R, Federici S, Buoncompagni A, Plebani A, Merlini G, and Martini A (2008) Persistent efficacy of anakinra in patients with tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum 58:1516–1520CrossRefPubMedGoogle Scholar
  28. 28.
    Siebert S, Amos N, and Lawson TM (2008) Comment on: failure of anti-TNF therapy in TNF receptor 1-associated periodic syndrome (TRAPS). Rheumatology (Oxford) 47:228–229CrossRefGoogle Scholar
  29. 29.
    Jacobelli S, Andre M, Alexandra JF, Dode C, and Papo T (2007) Failure of anti-TNF therapy in TNF Receptor 1-Associated Periodic Syndrome (TRAPS). Rheumatology (Oxford) 46:1211–1212CrossRefGoogle Scholar
  30. 30.
    Drewe E, Powell RJ, and E. M. McDermott (2007) Comment on: failure of anti-TNF therapy in TNF receptor 1-associated periodic syndrome (TRAPS). Rheumatology (Oxford) 46:1865–1866CrossRefGoogle Scholar
  31. 31.
    Boms S, Sehr T, Jappe U, and Enk A (2008) [First manifestation of psoriasis vulgaris in tumor necrosis factor receptor-associated periodic syndrome during treatment with etanercept]. Hautarzt 59:653–655CrossRefPubMedGoogle Scholar
  32. 32.
    Siebert S, Fielding CA, Williams BD, and Brennan P (2005) Mutation of the extracellular domain of tumour necrosis factor receptor 1 causes reduced NF-kappaB activation due to decreased surface expression. FEBS Lett 579:5193–5198CrossRefPubMedGoogle Scholar
  33. 33.
    Yousaf N, Gould DJ, Aganna E, Hammond L, Mirakian RM, Turner MD, Hitman GA, McDermott MF, and Chernajovsky Y (2005) Tumor necrosis factor receptor I from patients with tumor necrosis factor receptor-associated periodic syndrome interacts with wild-type tumor necrosis factor receptor I and induces ligand-independent NF-kappaB activation. Arthritis Rheum 52:2906–2916CrossRefPubMedGoogle Scholar
  34. 34.
    Todd I, Radford PM, Ziegler-Heitbrock L, Ghaemmaghami AM, Powell RJ, and Tighe PJ (2007) Elevated CD16 expression by monocytes from patients with tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum 56:4182–4188CrossRefPubMedGoogle Scholar
  35. 35.
    D’Osualdo A, Ferlito F, Prigione I, Obici L, Meini A, Zulian F, Pontillo A, Corona F, Barcellona R, Di Duca M, Santamaria G, Traverso F, Picco P, Baldi M, Plebani A, Ravazzolo R, Ceccherini I, Martini A, and Gattorno M (2006) Neutrophils from patients with TNFRSF1A mutations display resistance to tumor necrosis factor-induced apoptosis: pathogenetic and clinical implications. Arthritis Rheum 54:998–1008CrossRefPubMedGoogle Scholar
  36. 36.
    Nedjai B, Hitman GA, Quillinan N, Coughlan RJ, Church L, McDermott MF, and Turner MD (2009) Proinflammatory action of the antiinflammatory drug infliximab in tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum 60:619–625CrossRefPubMedGoogle Scholar
  37. 37.
    Nedjai B, Hitman GA, Yousaf N, Chernajovsky Y, Stjernberg-Salmela S, Pettersson T, Ranki A, Hawkins PN, Arkwright PD, M. F. McDermott, and Turner MD (2008) Abnormal tumor necrosis factor receptor I cell surface expression and NF-kappaB activation in tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum 58:273–283CrossRefPubMedGoogle Scholar
  38. 38.
    Churchman SM, Church LD, Savic S, Coulthard LR, Hayward B, Nedjai B, Turner MD, Mathews RJ, Baguley E, Hitman GA, Gooi HC, Wood PM, Emery P, and McDermott MF (2008) A novel TNFRSF1A splice mutation associated with increased nuclear factor kappaB (NF-kappaB) transcription factor activation in patients with tumour necrosis factor receptor associated periodic syndrome (TRAPS). Ann Rheum Dis 67:1589–1595CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Susana L. Rebelo
    • 1
  • Paul M. Radford
    • 1
  • Susan E. Bainbridge
    • 1
  • Ian Todd
    • 1
  • Patrick J. Tighe
    • 1
  1. 1.Institute of Infection, Immunity & Inflammation, and School of Molecular Medical Sciences, University of Nottingham; Immunology, A Floor West Block, Queen’s Medical CentreNottinghamUK

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